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4. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

Author

Petersdorf, Effie W, Carrington, Mary, O'hUigin, Colm, Bengtsson, Mats, De Santis, Dianne, Dubois, Valerie, Gooley, Ted, Horowitz, Mary, Hsu, Katharine, Madrigal, J Alejandro, Maiers, Martin, Malkki, Mari, McKallor, Caroline, Morishima, Yasuo, Oudshoorn, Machteld, Spellman, Stephen, Villard, Jean, Stevenson, Phil, Apperley, Jane, Bardy, Peter, Bernard, Ghislaine, Bertrand, Yves, Bloor, Adrian, Bonini, Chiara, Buhler, Stephane, Bungener, Laura, Campbell, Helen, Carlson, Kristina, Carpenter, Ben, Cesbron, Anne, Chabannon, Christian, Chalandon, Yves, Chapman, Jeremy, Chebel, Réda, Chevallier, Patrice, Choi, Gerda, Collin, Matt, Cornelissen, Jan J, Crawley, Charles, D'Orsogna, Lloyd, Dalle, Jean-Hugues, Deconinck, Eric, DeMatteis, Muriel, Diviney, Mary, Dormoy, Anne, Gagne, Katia, Gibson, Brenda, Gilleece, Maria, Gottlieb, David, Gribben, John, Güngör, Tayfun, Haagenson, Mike, Hart, Cathie, Holdsworth, Rhonda, Humphreys, Ian, Kodera, Yoshihisa, Koh, Mickey, Labussière-Wallet, Hélène, Lankester, Arjan C, Lardy, Neubery, Lawson, Sarah, Leleu, Xavier, MacKinnon, Stephen, Malladi, Ram, Marsh, Steven GE, Martin, Murray, Mayor, Neema P, McQuaker, I Grant, Meijer, Ellen, Morishima, Satoko, Nikolousis, Emmanouil, Orchard, Kim, Passweg, Jacob, Patel, Amit, Patrick, Katherine, Pedron, Béatrice, Peniket, Andy, Perry, Julia, Petersen, Eefke, Potter, Victoria, Potter, Mike, Protheroe, Rachel, Raus, Nicole, Ruiz de Elvira, Carmen, Russell, Nigel, Schaap, Nicholaas PM, Schanz, Urs, Schouten, Harry, Skinner, Roderick, Snowden, John, Spierings, Eric, Steward, Colin, Tholouli, Eleni, Thornton, Alycia, Tilanus, Marcel, van de Meer, Arnold, Veelkens, Hendrik, Veys, Paul, Watson, Narelle, Weston, Lyanne, Wilson, Keith, Wilson, Marie, Wynn, Robert, Zsiros, József, Maiers, Martin J, and Spellman, Stephen R

Published
2020
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6. Nonparametric failure time: Time‐to‐event machine learning with heteroskedastic Bayesian additive regression trees and low information omnibus Dirichlet process mixtures.

Author

Sparapani, Rodney A., Logan, Brent R., Maiers, Martin J., Laud, Purushottam W., and McCulloch, Robert E.

Subjects
REGRESSION trees, HEMATOPOIETIC stem cells, STEM cell transplantation, PROPORTIONAL hazards models, MACHINE learning, SURVIVAL analysis (Biometry)
Abstract

Many popular survival models rely on restrictive parametric, or semiparametric, assumptions that could provide erroneous predictions when the effects of covariates are complex. Modern advances in computational hardware have led to an increasing interest in flexible Bayesian nonparametric methods for time‐to‐event data such as Bayesian additive regression trees (BART). We propose a novel approach that we call nonparametric failure time (NFT) BART in order to increase the flexibility beyond accelerated failure time (AFT) and proportional hazard models. NFT BART has three key features: (1) a BART prior for the mean function of the event time logarithm; (2) a heteroskedastic BART prior to deduce a covariate‐dependent variance function; and (3) a flexible nonparametric error distribution using Dirichlet process mixtures (DPM). Our proposed approach widens the scope of hazard shapes including nonproportional hazards, can be scaled up to large sample sizes, naturally provides estimates of uncertainty via the posterior and can be seamlessly employed for variable selection. We provide convenient, user‐friendly, computer software that is freely available as a reference implementation. Simulations demonstrate that NFT BART maintains excellent performance for survival prediction especially when AFT assumptions are violated by heteroskedasticity. We illustrate the proposed approach on a study examining predictors for mortality risk in patients undergoing hematopoietic stem cell transplant (HSCT) for blood‐borne cancer, where heteroskedasticity and nonproportional hazards are likely present. [ABSTRACT FROM AUTHOR]

Published
2023
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10. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation : a retrospective cohort study

Author

Petersdorf, Effie W., Carrington, Mary, O'hUigin, Colm, Bengtsson, Mats, De Santis, Dianne, Dubois, Valerie, Gooley, Ted, Horowitz, Mary, Hsu, Katharine, Madrigal, J. Alejandro, Maiers, Martin J., Malkki, Mari, McKallor, Caroline, Morishima, Yasuo, Oudshoorn, Machteld, Spellman, Stephen R., Villard, Jean, Stevenson, Phil, Petersdorf, Effie W., Carrington, Mary, O'hUigin, Colm, Bengtsson, Mats, De Santis, Dianne, Dubois, Valerie, Gooley, Ted, Horowitz, Mary, Hsu, Katharine, Madrigal, J. Alejandro, Maiers, Martin J., Malkki, Mari, McKallor, Caroline, Morishima, Yasuo, Oudshoorn, Machteld, Spellman, Stephen R., Villard, Jean, and Stevenson, Phil

Abstract

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, japan, North America, and the UK between jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50.3%) HLA-matched and 1457 (4.3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1.89, 95% CI 1. 53-2.33; p<0.0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1.73, 1.02-2.94; p=0 .042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (O

Published
2020
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11. Assessment of HLA-Bgenetic variation with an HLA-Bleader tool and implications in clinical transplantation

Author

Sajulga, Ray, Bolon, Yung-Tsi, Maiers, Martin J., and Petersdorf, Effie W.

Abstract

Sequence variation in the HLA-Bgene is critically linked to differential immune responses. A dimorphism at -21 of HLA-Bexon 1 gives rise to leader peptides that are markers for risk of acute graft-versus-host disease, relapse, and mortality after unrelated donor and cord blood transplantation. To optimize the selection of stem cell transplant sources based on the HLA-Bleader, an HLA-BLeader Assessment Tool (BLEAT) was developed to automate the assignment of leader genotypes, define HLA-Bleader match statuses, and rank order candidate stem cell sources according to clinical risk. The base cohort consisted of 9 417 614 registered donors from the Be The Match Registry with HLA-Btyping. Among these donors, the performance of BLEAT was assessed in 1 098 358 donors with sequence data for HLA-Bexon 1 (2 196 716 haplotypes). The accuracy of leader assignment was then assessed in a second cohort of 1259 patients and their unrelated transplant donors. We furthermore established the frequencies of HLA-Bleader genotype (MM, MT, TT) representations in broad racial categories in the 9.42 million donors. BLEAT has direct applications for the selection of optimal stem cell sources for transplantation and broad utility in basic and clinical research in pharmacogenomics, vaccine development, and cancer and infectious disease studies of human populations.

Published
2022
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12. Role of HLA-Bexon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

Author

Petersdorf, Effie W, Carrington, Mary, O'hUigin, Colm, Bengtsson, Mats, De Santis, Dianne, Dubois, Valerie, Gooley, Ted, Horowitz, Mary, Hsu, Katharine, Madrigal, J Alejandro, Maiers, Martin J, Malkki, Mari, McKallor, Caroline, Morishima, Yasuo, Oudshoorn, Machteld, Spellman, Stephen R, Villard, Jean, Stevenson, Phil, Petersdorf, Effie W, Carrington, Mary, O'hUigin, Colm, Bengtsson, Mats, De Santis, Dianne, Dubois, Valerie, Gooley, Ted, Horowitz, Mary, Hsu, Katharine, Madrigal, J Alejandro, Maiers, Martin, Malkki, Mari, McKallor, Caroline, Morishima, Yasuo, Oudshoorn, Machteld, Spellman, Stephen, Villard, Jean, Stevenson, Phil, Apperley, Jane, Bardy, Peter, Bernard, Ghislaine, Bertrand, Yves, Bloor, Adrian, Bonini, Chiara, Buhler, Stephane, Bungener, Laura, Campbell, Helen, Carlson, Kristina, Carpenter, Ben, Cesbron, Anne, Chabannon, Christian, Chalandon, Yves, Chapman, Jeremy, Chebel, Réda, Chevallier, Patrice, Choi, Gerda, Collin, Matt, Cornelissen, Jan J, Crawley, Charles, D'Orsogna, Lloyd, Dalle, Jean-Hugues, Deconinck, Eric, DeMatteis, Muriel, Diviney, Mary, Dormoy, Anne, Gagne, Katia, Gibson, Brenda, Gilleece, Maria, Gottlieb, David, Gribben, John, Güngör, Tayfun, Haagenson, Mike, Hart, Cathie, Holdsworth, Rhonda, Humphreys, Ian, Kodera, Yoshihisa, Koh, Mickey, Labussière-Wallet, Hélène, Lankester, Arjan C, Lardy, Neubery, Lawson, Sarah, Leleu, Xavier, MacKinnon, Stephen, Malladi, Ram, Marsh, Steven GE, Martin, Murray, Mayor, Neema P, McQuaker, I Grant, Meijer, Ellen, Morishima, Satoko, Nikolousis, Emmanouil, Orchard, Kim, Passweg, Jacob, Patel, Amit, Patrick, Katherine, Pedron, Béatrice, Peniket, Andy, Perry, Julia, Petersen, Eefke, Potter, Victoria, Potter, Mike, Protheroe, Rachel, Raus, Nicole, Ruiz de Elvira, Carmen, Russell, Nigel, Schaap, Nicholaas PM, Schanz, Urs, Schouten, Harry, Skinner, Roderick, Snowden, John, Spierings, Eric, Steward, Colin, Tholouli, Eleni, Thornton, Alycia, Tilanus, Marcel, van de Meer, Arnold, Veelkens, Hendrik, Veys, Paul, Watson, Narelle, Weston, Lyanne, Wilson, Keith, Wilson, Marie, Wynn, Robert, and Zsiros, József

Abstract

The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-Bgives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT.

Published
2020
Full Text
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